DESCRIPTION (applicant's abstract): There is a large body of evidence that the immune system is functionally integrated with both the nervous and endocrine systems. This integration plays a key role in regulating both the innate and adaptive immune responses to a variety of infectious agents. The long-range goal of this program is to define the neuroendocrine and immune mechanisms by which psychological stress affects T cell-based immune responses to herpes simplex virus (HSV) infections. The main objective of this proposal is to determine how products of the hypothalamic- pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) associated with psychological stress modulate the generation and activation of memory cytotoxic T lymphocytes (CTLm) and to what extent this modulation is mediated by the effects of these products on antigen processing and presentation. The rationale for the proposed research is based on the fact that CTLm play key roles in mediating protection against not only recurrent HSV infection but also other viral infections. Moreover, the efficiency with which virus-encoded CTL recognition epitopes are processed and presented by antigen presenting cells (APC) is central to both the generation and activation of these CTLm. To achieve this objective, three specific aims are proposed: (1) To determine the impact of stress and stress-associated activation of the HPA axis and SNS on the generation of HSV-specific memory CTL; (2) To evaluate the effects of stress and stress-associated activation of the HPA axis and SNS on the activation and function of HSV-specific memory CTL in vivo; and (3) To determine the role of corticosterone and beta-2 adrenergic receptor agonists on molecular components of antigen processing and presentation. At the completion of this project we expect to have determined that the effects of the stress on the magnitude of the CTLm response depend on both the nature of the vector delivering the CTL epitope as well as the immunogenicity of the epitope itself. We also expect that stress will diminish the protective ability of HSV-specific CTLm in vivo at both peripheral sites and in the central nervous system. We anticipate that one or more of the molecular components involved in antigen processing and presentation will be affected by corticosterone and/or beta-2 adrenergic receptor agonists. Overall, these studies will define the impact of stress and associated HPA axis- and SNS-derived products on HSV-specific CTLm activation and function and will provide insight into the molecular mechanisms by which stress effects immune-based protection to viral infection.